Megan Clowse

A national study of the complications of lupus in pregnancy

OBJECTIVE This study was undertaken to determine the risk of rare complications during pregnancy for women with systemic lupus erythematosus. STUDY DESIGN By using the Nationwide Inpatient Sample from 2000-2003, we compared maternal and pregnancy complications for all pregnancy-related admissions for women with and without systemic lupus erythematosus. RESULTS Of more than 16.7 million admissions for childbirth over the 4 years, 13,555 were to women with systemic lupus erythematosus. Maternal mortality was 20-fold higher among women with systemic lupus erythematosus. The risks for thrombosis, infection, thrombocytopenia, and transfusion were each 3- to 7-fold higher for women with systemic lupus erythematosus. Lupus patients also had a higher risk for cesarean sections (odds ratio: 1.7), preterm labor (odds ratio: 2.4), and preeclampsia (odds ratio: 3.0) than other women. Women with systemic lupus erythematosus were more likely to have other medical conditions, including diabetes, hypertension, and thrombophilia, that are associated with adverse pregnancy outcomes. CONCLUSION Women with systemic lupus erythematosus are at increased risk for serious medical and pregnancy complications during pregnancy.

Ovarian Preservation by GnRH Agonists during Chemotherapy: A Meta-Analysis

PURPOSE Treatment with cyclophosphamide (CYC) confers up to a 40% risk of ovarian failure in women of reproductive age. The use of GnRH agonists (GnRHa) to preserve ovarian function has been investigated in several small studies. We performed a systematic review of studies examining whether a GnRHa administered during chemotherapy is protective of ovarian function and fertility. METHODS We searched the English-language literature (1966-April 2007) using MEDLINE and meeting abstracts and included studies that reported an association between GnRHa and ovarian preservation in women receiving chemotherapy. Studies without a control group were excluded. Ovarian preservation was defined as the resumption of menstrual cycles and a premenopausal follicle-stimulating hormone (FSH) after chemotherapy. Fertility was determined by a womans ability to become pregnant. We estimated the summary relative risk (RR) and associated 95% confidence intervals (95% CI) using a random-effects model. RESULTS Nine studies included 366 women. Three studies included women with autoimmune disease receiving CYC; six included women with hematologic malignancy receiving combination chemotherapy. In total, 178 women were treated with GnRHa during chemotherapy, 93% of whom maintained ovarian function. Of the 188 women not treated with GnRHa, 48% maintained ovarian function. The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR = 1.68, 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR = 1.65, CI 1.03-2.6). CONCLUSIONS Based on the available studies, GnRHa appear to improve ovarian function and the ability to achieve pregnancy following chemotherapy. Several randomized trials are underway to define the role and mechanism of GnRHa in ovarian function preservation. In the meantime, premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.

Early risk factors for pregnancy loss in lupus

OBJECTIVE: To identify early risk factors for pregnancy loss in lupus pregnancies. METHODS: We conducted a cohort study of all pregnancies seen in the first trimester in lupus patients followed from 1987 to 2002 at the Hopkins Lupus Center. At each visit, vital signs, a complete blood count, a urinalysis, and a 24-hour urine collection for total protein, if the dipstick revealed proteinuria, were obtained. Proteinuria was defined as protein greater than 500 mg in a 24-hour urine collection. Secondary antiphospholipid syndrome was diagnosed by using the Sapporo criteria. Thrombocytopenia was defined as platelets under 150,000. Hypertension was defined as blood pressure over 140/90 mm Hg during the first trimester. Pregnancies electively terminated were excluded from this study. RESULTS: One hundred sixty-six pregnancies in 125 women were followed in the Hopkins Lupus Cohort from the first trimester onward. Twenty-seven pregnancies (16%) ended with a loss. Pregnancy loss was increased 2.6 times in women with first-trimester proteinuria (P = .04). A diagnosis of secondary antiphospholipid syndrome led to a 3.1-fold increase in pregnancy loss, predominantly after 20 weeks of gestation (P = .004). Thrombocytopenia in the first trimester led to an increase in pregnancy loss by 3.3 fold (P ≤ .001). First-trimester hypertension led to a 2.4-fold increase in pregnancy loss (P = .027). Each risk factor was independent in raising pregnancy loss risk. CONCLUSION: The acronym PATH can help remind clinicians to monitor for Proteinuria, Antiphospholipid syndrome, Thrombocytopenia, and Hypertension early in pregnancy. Close observation, with frequent laboratory analysis and appropriate therapy, is important to pregnancy success in women with lupus. LEVEL OF EVIDENCE: II-2

Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by antibodies to DNA and other nuclear molecules. While these antibodies can form immune complexes, the mechanisms generating the bound nuclear antigens are not known. These studies investigated whether microparticles can form complexes with anti-DNA and other anti-nucleosomal antibodies. Microparticles are small membrane-bound vesicles released from dead and dying cells; these particles contain a variety of cellular components, including DNA. To assess antigenicity, microparticles generated in vitro from apoptotic cell lines were tested using murine monoclonal anti-DNA and anti-nucleosomal antibodies as well as plasma from lupus patients. Antibody binding was assessed by flow cytometry. As these studies showed, some but not all of the monoclonal antibodies bound to microparticles prepared from apoptotic HL-60, THP-1 and Jurkat cells. For HL-60 cells, both staurosporine and UV radiation led to the production of antigenically active particles. For the anti-DNA antibody with high particle binding, prior treatment of DNase reduced activity. With plasma from patients with SLE, antibody binding to microparticles was present although a clear relationship with anti-DNA antibody levels was not observed. To determine whether lupus plasma contains immune complexes with particle properties, particle preparations were tested for bound IgG by flow cytometry. These studies indicated that lupus plasma contains particles with IgG binding, with numbers correlated with anti-DNA levels. Together, these findings indicate that microparticles display DNA and nucleosomal molecules in an antigenic form and could represent a source of immune complexes in SLE.

State of the art: reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their childrens birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

Cyclophosphamide for lupus during pregnancy.

Severe systemic lupus erythematosus often requires the use of cyclophosphamide in women of reproductive age. As cyclophosphamide is generally avoided during pregnancy because of its teratogenic risk, its impact on fetal survival is poorly understood. This is a case series of lupus patients exposed to cyclophosphamide during pregnancy. We reviewed pregnancies in patients with lupus seen at a large university hospital between October 1986 and September 2003. The pregnancies were evaluated prospectively for cyclophosphamide exposure, lupus activity, and fetal outcome. Comparison was made between pregnancies with severe lupus requiring cyclophosphamide and those that did not. We identified four pregnancies with cyclophosphamide exposure. Two pregnancies were inadvertently exposed to cyclophosphamide early in the first trimester; both resulted in first trimester miscarriages. Two patients were administered cyclophosphamide for severe lupus nephritis and thrombocytopenia during the second trimester. Soon after the administration of cyclophosphamide, both pregnancies ended with fetal demise. Pregnancies exposed to cyclophosphamide for severe lupus flare resulted in a higher rate of fetal losses than pregnancies with severe lupus but not requiring the drug (100% versus 31.25%). In conclusion we present four pregnancies exposed to cyclphosphamide, each ending with pregnancy loss. Based on our experience, the survival of the fetus is strongly in doubt when cyclophosphamide is required to treat lupus in the mother.

Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus

Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children on average than other women. We sought to determine the roles of infertility, pregnancy loss, and personal choice on family size in women with these diseases.

The Clinical Utility of Measuring Complement and Anti-dsDNA Antibodies During Pregnancy in Patients with Systemic Lupus Erythematosus

Objective. The importance of low complement and anti-dsDNA during pregnancy in patients with systemic lupus erythematosus (SLE) is poorly defined. We investigated the effect of these laboratory tests and clinical SLE activity on pregnancy outcomes. Methods. We conducted a study of all pregnancies in patients with SLE followed from 1986 to 2002 in a cohort of patients with SLE. At each visit, the physician’s estimate of activity (PEA), complement, and anti-dsDNA antibody were measured. We assessed the combination of moderate to severe SLE clinical activity (defined as PEA ≥ 2) and these serologic measurements on pregnancy outcomes. Pregnancies electively terminated were excluded from our study. Results. Regardless of SLE activity, low complement or positive anti-dsDNA in the second trimester was associated with a higher rate of pregnancy loss and preterm birth. Patients with the combination of either high clinical activity of SLE and low complement or positive anti-dsDNA had the highest rate of pregnancy loss and preterm birth. Conclusion. Women with the combination of high clinical activity with serologic markers of SLE activity are at highest risk for pregnancy loss and preterm delivery. While hypocomplementemia and positive anti-dsDNA alone are predictive of poor pregnancy outcomes in the second trimester, the risks are far higher for the women in whom this is coupled with clinically active SLE.

An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1.

Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1-infected individuals with autoimmune disease and defective immune tolerance mechanisms may produce BnAbs more readily than those without autoimmune diseases. In this study, we identified an HIV-1-infected individual with SLE who exhibited controlled viral load (<5,000 copies/ml) in the absence of controlling HLA phenotypes and developed plasma HIV-1 neutralization breadth. We collected memory B cells from this individual and isolated a BnAb, CH98, that targets the CD4 binding site (CD4bs) of HIV-1 envelope glycoprotein 120 (gp120). CH98 bound to human antigens including dsDNA, which is specifically associated with SLE. Anti-dsDNA reactivity was also present in the patients plasma. CH98 had a mutation frequency of 25% and 15% nt somatic mutations in the heavy and light chain variable domains, respectively, a long HCDR3, and a deletion in the light chain CDR1. The occurrence of anti-dsDNA reactivity by a HIV-1 CD4bs BnAb in an individual with SLE raises the possibility that some BnAbs and SLE-associated autoantibodies arise from similar pools of B cells.

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Standard treatment for severe granulomatosis with polyangiitis (Wegeners) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).